Astrocytomas, brain tumors originating from differentiated astrocytes, show a tendency for progression towards a more malignant phenotype. Astrocytomas are classified, according to the WHO malignancy scale, into low-grade astrocytoma (WHO Grade II; “AII”), anaplastic astrocytoma (WHO Grade III; “AIII”), and glioblastoma multiforme (WHO Grade IV; “GBM”). GBM, the most common form of primary brain tumor, carries a very poor prognosis even after surgical resection with subsequent radio- and chemotherapy.
Small ubiquitin-like modifier (SUMO) proteins are a group of small proteins that bind lysine residues of target proteins and thereby modify target protein activity, stability, and sub-cellular localization. SUMO2 and SUMO3 proteins share a high degree of similarity (95% sequence identity), but are relatively distinct from SUMO1 (only 50% sequence identity). Like ubiquitin, SUMO protein is synthesized as a larger precursor protein that is processed by sentrin-specific proteases (SENPs) to expose the two C-terminal glycine residues that provide for conjugation. SUMO conjugation (or “sumoylation”) is a highly volatile process, with various enzymes involved in the conjugation, e.g., E1, E2 and Ubc9, and de-conjugating (or “de-sumoylation”) e.g., SENPs, processes. A large portion of SUMO conjugation targets transcription factors and other nuclear proteins involved in gene expression. A major change in levels of SUMO conjugated proteins may have a major impact on the fate of cells.